SUDDEN DEATH

1
SUDDEN DEATH ANTIPSYCHOTIC DRUGS

• Homayoun Amini M.D.
• TUMS

2
Introduction

• In recent years many clinicians have become
  increasingly troubled over reports of sudden,
  unexplained death occurring in psychiatric
  patients being treated with phenothiazine
  tranquilizing drugs. Most cases reported are
  young, in apparent good health, on fairly high
  doses of one or more phenothiazines
  (Leestma
  Koenig, 1968)

3
Epidemiology

• The death rate among psychiatric patients tends
  to be higher than that of the general population,
  but suicide and accidental deaths may account for
  much of this excess (Tsuang Woolson, 1978
  Black Fisher, 1992).
• Sudden, unexpected death is perhaps more common
  in the general population than might be expected.
  It has been estimated that between 1530 of all
  natural fatalities in the industrially developed
  world occur suddenly and unexpectedly (Kannel et
  al, 1975 Gullestad Kjekshus, 1992).

4
Epidemiology

• Estimates of the total number of sudden,
  unexpected natural deaths in the United States
  alone range from 300,000 to 500,000/year (Doyle,
  1976 Horowitz and Morganroth, 1982 Kannel and
  Thomas, 1982)

5
Definition

• Sudden, unexpected, unexplained death can be
  defined as death within one hour of symptoms
  (excluding suicide, homicide and accident)
  (Ungvari, 1980) which is both unexpected in
  relation to the degree of disability before death
  (Kuller et al, 1967) and unexplained because
  clinical investigation and autopsy failed to
  identify any plausible cause (Hirsch Martin,
  1971).

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Mental disorders Mortality

• The risk of premature death among psychiatric
  patients is higher than in the general population
• A psychiatric Dx per se increases the risk of
  dying prematurely
• Psychiatric patients are at increased risk of
  death from a number of natural causes

7
Mental disorders Mortality

• High natural mortality in schizophrenia results
  from a variety of lifestyle factors Smoking,
  exercise, care, nutrition, BMI, BP, Chol
• After adjustment for these factors the excess
  mortality persisted

8
Report of the Working Group of the Royal College
ofPsychiatrists Psychopharmacology
Sub-GroupCouncil Report CR 57Approved by
Council January 1997

• There are insufficient data to prove that sudden
  death is more likely among people being treated
  with antipsychotic medication than it is among
  the general population.
• However, there are no data that prove there is no
  causal relationship between the use of this group
  of drugs and sudden death.

9
An American Psychiatric Association Task Force
Report

• The studies in Hungary, U.S.A. and China show no
  evidence for an increase in sudden death in
  patients receiving psychotropic medications.
• This does not mean, however, that the question of
  a relationship between the administration of
  psychotropic agents and sudden death has been
  answered.

10
Ray et al., 2001

• Prescription of moderate doses of antipsychotics
  was associated with large relative and absolute
  increases in the risk of sudden cardiac death

11
The association between sudden, unexpected
deathand antipsychotic drugs

• Non-cardiac etiologies including asphyxia
  chocking convulsions
  hyperpyrexia psychological
  stress restraint

12
The association between sudden, unexpected
deathand antipsychotic drugs

• Cardiac etiologies hypertrophic
  cardiomyopathy congenital structural
  abnormalities coronary artery disease
  arrhythmia

13
Cardiac effects of antipsychotic drugs

• Abnormalities of the electrocardiogram (ECG) are
  relatively common in people receiving
  neuroleptics, occurring in around 25
• There are numerous reports of ventricular
  arrhythmias associated with repolarisation
  disturbances such as prolonged QT intervals,
  widening of QRS complexes, depression of ST
  segments and most commonly abnormal T-morphology
  or large U-waves

14
Cardiac effects of antipsychotic drugs

• observed more often in patients with pre-existing
  heart disease
• phenothiazine group of antipsychotics display
  electrophysiological properties like those of the
  class IA antiarrhythmic agents (quinidine-like),
  involving blockade of potassium and sodium
  channels, leading to a prolonged duration of the
  action potential (which also slows conduction),
  refractory period and QT interval

15
Cardiac effects of antipsychotic drugs

• These ECG changes have commonly been considered
  benign, and even now there is no consensus on the
  clinical significance of prolonged QTc
• However, QT prolongation has been shown to
  produce serious arrhythmias that have sometimes
  proved fatal

16
Cardiac effects of antipsychotic drugs

• Heart rates and autonomic activity alter
  radically during sleep, and that sleep recordings
  may detect pathological markers of arrhythmia
• There is a relationship between rising drug dose,
  lengthening QT interval and increasing risk, but
  that the relationship is not linear and deaths
  can occur when these parameters are apparently
  within normal limits

17
Cardiac effects of antipsychotic drugs

• Apparently benign QT prolongation in one subject
  may indicate that another more susceptible
  patient might develop extreme QT prolongation and
  arrhythmias with the same drug at the same dose.
• Although the increased risk is probably small,
  because minor QT prolongation is common the risk
  is applied over a large population.

18
Cardiac effects of antipsychotic drugs

• There are reports of torsade de pointes when the
  drug dose has been well within the therapeutic
  range
• CYP2D6 is a hydroxylase enzyme which is deficient
  in 510 of the Caucasian population.

19
Risk Factors

• Underlying cardiac disease
• Concurrent drug treatment diuretics,
• Illicit drugs
• Electrolyte imbalances hypokalemia,
• Restraint
• More than one neuroleptic
• High dosage

20
Conclusions

• Death among psychiatric inpatients has decreased
  since the introduction of psychotropic drugs but
  is still higher than in the general population.
• Sudden death has not increased since the
  introduction of psychotropic drugs.
• Independent studies from three different
  countries find no differences in mortality in
  patients given antipsychotic agents compared to
  the general population.

21
Conclusions

• All hospitals with psychiatric beds should have a
  protocol for investigating all cases of sudden,
  unexpected deaths. One provision of such policy
  should be the encouragement of an autopsy which
  would include microscopic examination of the
  conduction pathways and coronary vasculature of
  the heart.

22
Conclusions

• Restraint orders must be issued by a physician
  after seeing the patient and patients should be
  closely monitored by nurses and paramedical
  staff.
• Case conferences should be held to discuss and
  focus on restraint

23
Conclusions

• The properly designed epidemiological studies
  that might determine the role of these drugs in
  sudden death have not been done and are probably
  not possible because of logistical and financial
  considerations.
• To reduce the risk to zero in any population is
  idealistic but unrealistic and impossible. To
  minimize risk is certainly a desirable goal.

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Recommendations

• An ECG is advisable, and any abnormality should
  be carefully assessed,
• Use the lowest effective doses of antipsychotic
  drugs
• The drug dose should be increased gradually
• Using benzodiazepines to compliment
  antipsychotics in the acute phases of treatment
  are promising in that lower doses of the latter
  are possible

25
Recommendations

• A well-trained staff in a quiet, comfortable,
  well-ventilated, temperature controlled setting
  will result in a reduction in the amount of
  antipsychotic drug needed to control behavior
• Providing sufficient time for patients to eat and
  to training in proper eating habits
• Staff should be familiar with the Heimlich
  maneuver and other antichoking techniques
• Regular monitoring of vital signs is essential
  (including temperature, pulse and postural blood
  pressure)

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APA Task ForceReport

• if a balanced perspective is not maintained, it
  is all too tempting to conclude that any sudden
  death occurring in the presence of an
  antipsychotic drug is due to the drug, and that
  any sudden death occurring in a drug free patient
  could have been prevented by the use of a drug.